The presenilins are proteins of little known function which are involved in the etiology of Alzheimer's disease (AD). These proteins appear to be involved in development (particularly neural progenitor cell survival and neurogenesis), survival forms of apoptosis, and Abeta formation. There is evidence indicating that at least some of the effects of presenilins are mediated by the interaction of the COOH-terminus of these proteins with a cytoplasmic protein. For this reason, we have used the two-hybrid system to identify proteins interacting with the COOH- terminus of the presenilins and have found a novel protein which we call "calsenilin". Our results indicate that the presenilins associate with calsenilin in situ and that calsenilin regulates the level of presenilin fragments. These data implicate calsenilin in the biology of the presenilins. Calsenilin is a novel member of the recovering family. Members of this family are calcium binding proteins which appear to play a role in modulating signaling transduction cascades in response to calcium signals. Our broad, long-term goal is to understand the normal function of the presenilins and to understand the molecular of their role in AD. As step towards this goal, we have identified a protein (calsenilin) which interacts with the domain of the presinilins which has been postulated as interacting with other proteins in order to exert biological effects. The next step would be to characterize the function of calsenilin, to study its role in presenilin-mediated effects, and to examine calsenilin in AD. From these studies, the role of calsenilin in presenilin biology and AD will be clarified. In the current proposal, we will take advantage of the unique resources of the ARDC to accomplish these goals. The specific aims are as follows: 1. To localize calsenilin in the rat and primate nervous system. 2. To determine the relationship between the distribution of calsenilin, presenilin, neurofibrillary pathology, Abeta deposition, glutamatergic receptor subtypes and dying neurons in AD brain. 3. To characterize neural development of nice in which the calsenilin gene has been disrupted. 4. To characterize presenilin levels, Abeta formation and Abeta accumulation in mice in which the calsenilin gene has been disrupted.